Tuberculosis (TB) is the leading cause of death by an infectious disease in the world. The synergy between TB and AIDS is also very apparent. TB is also the primary cause of death for individuals co-infected with the human immunodeficiency virus (HIV). HIV infection is the greatest single risk factor known for progression from TB infection to active TB disease: in developing nations, as many as 40-80% of individuals with the acquired immunodeficiency syndrome (AIDS) will also develop TB. Conversely, co-infected patients with active TB show enhanced viral replication and accelerated progression of AIDS. Although TB is a treatable, current chemotherapy regimens require a complex strategy of 3 drugs for least six months. Such prolonged therapy is necessary because conventional drugs are poorly effective against a sub-population of patent and drug-tolerant bacterial 'persisters'. Most patients will not adhere to this treatment regimen. Patients who default suffer increased rates of treatment failure, relapse, and drug resistence. New drugs against persisting mycobacteria are urgently needed to counter the problem of patient non-compliance. The development of new drugs would be greatly facilitated by the identification of bacterial non- compliance. The development of new drugs would be greatly facilitated by the identification of bacterial 'persistence factors' as candidate drug targets. A significant step towards this goal was our recent demonstration that the glyoxylate shunt enzyme, isocitrate lyase, ICL, is essential for persistence of demonstration that the glyoxylate shunt enzyme isocitrate lyase, ICL, is essential for persistence of Mycobacterium tuberculosis, in vivo. In addition, we have demonstrated the ICL is expressed at high levels in M. tuberculosis living in murine macrophages. Building on these observation, we will take a multi-discipline approach to define the role of the glyoxylate shunt and fatty acid catabolism in persistence. Enzymes found essential to persistent organisms will be characterized and used in high throughput drug screening and structure based drug-design. Promising lead compounds will be tested for safety and efficacy in a mouse model of chemotherapy, latency, and relapse. Indeed, the primary goal of this proposal is to develop new chemotherapeutics for the treatment of persistent M. tuberculosis infections.